scholarly journals Differential Effects of Penicillin Binding Protein Deletion on the Susceptibility of Enterococcus faecium to Cationic Peptide Antibiotics

2015 ◽  
Vol 59 (10) ◽  
pp. 6132-6139 ◽  
Author(s):  
George Sakoulas ◽  
Monika Kumaraswamy ◽  
Poochit Nonejuie ◽  
Brian J. Werth ◽  
Micahel J. Rybak ◽  
...  
Keyword(s):  
Enterococcus Faecium ◽  
Cumulative Effect ◽  
Human Neutrophils ◽  
Peptide Antibiotics ◽  
Penicillin Binding Protein ◽  
Beta Lactam ◽  
Content Type ◽  
Penicillin Binding Proteins ◽  
Beta Lactam Antibiotics ◽  
Knockout Mutants

ABSTRACTBeta-lactam antibiotics sensitizeEnterococcus faeciumto killing by endogenous antimicrobial peptides (AMPs) of the innate immune system and daptomycin through mechanisms yet to be elucidated. It has been speculated that beta-lactam inactivation of selectE. faeciumpenicillin binding proteins (PBPs) may play a pivotal role in this sensitization process. To characterize the specific PBP inactivation that may be responsible for these phenotypes, we utilized a previously characterized set ofE. faeciumPBP knockout mutants to determine the effects of such mutations on the activity of daptomycin and the AMP human cathelicidin (LL-37). Enhanced susceptibility to daptomycin was dependent more on a cumulative effect of multiple PBP deletions than on inactivation of any single specific PBP. Selective knockout of PBPZ renderedE. faeciummore vulnerable to killing by both recombinant LL-37 and human neutrophils, which produce the antimicrobial peptide in high quantities. Pharmacotherapy targeting multiple PBPs may be used as adjunctive therapy with daptomycin to treat difficultE. faeciuminfections.

scholarly journals Genomic Sequence of the Strain Enterococcus faecium ICIS 18

2020 ◽  
Vol 9 (2) ◽  
Author(s):  
M. V. Sycheva ◽  
L. P. Popova ◽  
T. M. Pashkova ◽  
Y. A. Khlopko ◽  
O. L. Kartashova ◽  
...  
Keyword(s):  
Genome Sequence ◽  
Enterococcus Faecium ◽  
Genomic Sequence ◽  
Draft Genome ◽  
Beta Lactam ◽  
Human Feces ◽  
Content Type ◽  
Beta Lactam Antibiotics ◽  
Genes Encoding ◽  
Feces Analysis

We report here the draft genome sequence of Enterococcus faecium strain ICIS 18, which was isolated from human feces. Analysis of the E. faecium ICIS 18 genome revealed genes encoding resistance to metals, fluoroquinolones, and beta-lactam antibiotics.

scholarly journals Target for bacteriostatic and bactericidal activities of beta-lactam antibiotics against Escherichia coli resides in different penicillin-binding proteins.

1995 ◽  
Vol 39 (4) ◽  
pp. 812-818 ◽  
Author(s):  
G Satta ◽  
G Cornaglia ◽  
A Mazzariol ◽  
G Golini ◽  
S Valisena ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Penicillin Binding Protein ◽  
Beta Lactam ◽  
Beta Lactams ◽  
Killing Effect ◽  
Penicillin Binding Proteins ◽  
Beta Lactam Antibiotics ◽  
Bactericidal Activities ◽  
The Given ◽  
The Relationship

The relationship between cell-killing kinetics and penicillin-binding protein (PBP) saturation has been evaluated in the permeability mutant Escherichia coli DC2 in which the antimicrobial activity of beta-lactams has been described as being directly related to the extent of saturation of the PBP target(s). Saturation of a single PBP by cefsulodin (PBP 1s), mecillinam (PBP 2), and aztreonam (PBP 3) resulted in a slow rate of killing (2.5-, 1.5-, and 0.8-log-unit decreases in the number of CFU per milliliter, respectively, in 6 h). Saturation of two of the three essential PBPs resulted in a marked increase in the rate of killing, which reached the maximum value when PBPs 1s and 2 were simultaneously saturated by a combination of cefsulodin and mecillinam (4.7-log-unit decrease in the number of CFU per milliliter in 6 h). Inactivation of all three essential PBPs by the combination of cefsulodin, mecillinam, and aztreonam further increased the killing kinetics (5.5-log-unit decrease in the number of CFU per milliliter), and this was not significantly changed upon additional saturation of the nonessential PBPs 5 and 6 by cefoxitin. Similar relationships between PBP saturation and killing kinetics were obtained with imipenem and meropenem at concentrations which inhibited only one PBP (PBP 2), only two PBPs (PBP 1s and 2), or all three essential PBPs. Saturation of one or more PBPs also resulted in a different rate of bacteriolysis, the highest rate being obtained by the cefsulodin-mecillinam combination and by 5 micrograms of either imipenem or meropenem per ml. All of these conditions caused saturation of PBP 2 and saturation or extensive binding of PBP 1s. However, none of these conditions caused determined the fastest possible rate of killing, which occurred only when all three essential PBPs were saturated. It was concluded that the actual killing effect of beta-lactams is reflected by killing rates that approach the fastest possible rate for the given microorganism and that the targets for the bactericidal activity are precisely those PBPs whose saturation or binding occurs under conditions.

scholarly journals Multidrug-resistant Staphylococcus cohnii and Staphylococcus urealyticus isolates from German dairy farms exhibit resistance to beta-lactam antibiotics and divergent penicillin-binding proteins

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Tobias Lienen ◽  
Arne Schnitt ◽  
Jens Andre Hammerl ◽  
Stephen F. Marino ◽  
Sven Maurischat ◽  
...  
Keyword(s):  
Antimicrobial Resistance ◽  
Gene Prediction ◽  
Dairy Farms ◽  
Multidrug Resistant ◽  
Amino Acid Sequences ◽  
Penicillin Binding Protein ◽  
Beta Lactam ◽  
Penicillin Binding Proteins ◽  
Antimicrobial Substances ◽  
Beta Lactam Antibiotics

AbstractNon-aureus staphylococci are commonly found on dairy farms. Two rarely investigated species are Staphylococcus (S.) cohnii and S. urealyticus. Since multidrug-resistant S. cohnii and S. urealyticus are known, they may serve as an antimicrobial resistance (AMR) gene reservoir for harmful staphylococcal species. In our study, nine S. cohnii and six S. urealyticus isolates from German dairy farms were analyzed by whole-genome sequencing and AMR testing. The isolates harbored various AMR genes (aadD1, str, mecA, dfrC/K, tetK/L, ermC, lnuA, fexA, fusF, fosB6, qacG/H) and exhibited non-wildtype phenotypes (resistances) against chloramphenicol, clindamycin, erythromycin, fusidic acid, rifampicin, streptomycin, tetracycline, tiamulin and trimethoprim. Although 14/15 isolates lacked the blaZ, mecA and mecC genes, they showed reduced susceptibility to a number of beta-lactam antibiotics including cefoxitin (MIC 4–8 mg/L) and penicillin (MIC 0.25–0.5 mg/L). The specificity of cefoxitin susceptibility testing for mecA or mecC gene prediction in S. cohnii and S. urealyticus seems to be low. A comparison with penicillin-binding protein (PBP) amino acid sequences of S. aureus showed identities of only 70–80% with regard to PBP1, PBP2 and PBP3. In conclusion, S. cohnii and S. urealyticus from selected German dairy farms show multiple resistances to antimicrobial substances and may carry unknown antimicrobial resistance determinants.

scholarly journals Kinetic properties of the Bacillus licheniformis penicillin-binding proteins

1995 ◽  
Vol 309 (1) ◽  
pp. 49-53 ◽  
Author(s):  
S Lepage ◽  
M Galleni ◽  
B Lakaye ◽  
B Joris ◽  
I Thamm ◽  
...  
Keyword(s):  
Bacillus Licheniformis ◽  
Accurate Determination ◽  
Kinetic Properties ◽  
Penicillin Binding Protein ◽  
Beta Lactam ◽  
Intact Cells ◽  
Penicillin Binding Proteins ◽  
Beta Lactam Antibiotics ◽  
Main Target

In the analysis of the interactions between beta-lactam antibiotics and their target enzymes, it is often difficult to estimate the kinetic properties of the molecules which react rapidly with their targets and in consequence behave as the most efficient antibiotics. The combined utilization of fluorescein-labelled penicillins and of a new competition method has allowed an accurate determination of the high second-order rate constants characterizing the acylation of Bacillus licheniformis penicillin-binding protein 1 (PBP1) by penicillins and cephalosporins. Strategies were devised for measuring high acylation rates while avoiding titration effects. The method was also suitable for measuring the PBP kinetic parameters in intact cells. These results also confirmed that PBP1 is probably the main target of most beta-lactam antibiotics. Cephalexin, however, reacted faster with PBP3.

scholarly journals Evolution and resistance expression of MRSA. Evaluation of beta-lactam antibiotics against a set of isogenic strains with different types of phenotypic expression.

1995 ◽  
Vol 42 (4) ◽  
pp. 517-524 ◽  
Author(s):  
K Asada ◽  
Y Inaba ◽  
E Tateda-Suzuki ◽  
K Kuwahara-Arai ◽  
T Ito ◽  
...  
Keyword(s):  
Meca Gene ◽  
Phenotypic Expression ◽  
Aminoglycoside Antibiotic ◽  
Penicillin G ◽  
Binding Affinities ◽  
Penicillin Binding Protein ◽  
Beta Lactam ◽  
Beta Lactam Antibiotics ◽  
Mrsa Infection ◽  
Resistance Expression

Methicillin-resistant Staphylococcus aureus (MRSA) has two mechanisms of resistance to beta-lactam antibiotics; one is mediated by mecA gene expression, and the other by penicillinase production. It has been generally accepted in the clinical field that beta-lactam antibiotics are not the drugs of choice for MRSA infection. In this report, however, ampicillin and penicillin G were shown to have relatively good activity against MRSA if combined with a beta-lactamase inhibitor, sulbactam. These beta-lactam antibiotics were found to have relatively high binding affinities to PBP2', the mecA-encoded MRSA-specific penicillin-binding protein. The possible therapeutic application of sulbactam/ampicillin against MRSA infection in combination with arbekacin, an aminoglycoside antibiotic newly developed and introduced into clinical use in Japan, is discussed.

scholarly journals In Vivo Activity of QPX7728, an Ultrabroad-Spectrum Beta-Lactamase Inhibitor, in Combination with Beta-Lactams against Carbapenem-Resistant Klebsiella pneumoniae

2020 ◽  
Vol 64 (11) ◽  
Author(s):  
Mojgan Sabet ◽  
Ziad Tarazi ◽  
David C. Griffith
Keyword(s):  
Klebsiella Pneumoniae ◽  
Beta Lactamase ◽  
Beta Lactam ◽  
Beta Lactams ◽  
Bacterial Killing ◽  
Clinical Issue ◽  
Content Type ◽  
Beta Lactam Antibiotics ◽  
Carbapenem Resistant ◽  
Lactamase Inhibitor

ABSTRACT Resistance to beta-lactams has created a major clinical issue. QPX7728 is a novel ultrabroad-spectrum cyclic boronic acid beta-lactamase inhibitor with activity against both serine and metallo-beta-lactamases developed to address this resistance for use in combination with beta-lactam antibiotics. The objective of these studies was to evaluate the activity of QPX7728 in combination with multiple beta-lactams against carbapenem-resistant Klebsiella pneumoniae isolates in a neutropenic mouse thigh infection model. Neutropenic mice were infected with strains with potentiated beta-lactam MICs of ≤2 mg/liter in the presence of 8 mg/liter QPX7728. Two strains of carbapenem-resistant K. pneumoniae were tested with aztreonam, biapenem, cefepime, ceftazidime, ceftolozane, and meropenem alone or in combination with 12.5, 25, or 50 mg/kg of body weight of QPX7728 every 2 hours for 24 hours. Treatment with all beta-lactams alone either was bacteriostatic or allowed for bacterial growth. The combination of QPX7728 plus each of these beta-lactams produced bacterial killing at all QPX7728 doses tested. Overall, these data suggest that QPX7728 administered in combination with different partner beta-lactam antibiotics may have utility in the treatment of bacterial infections due to carbapenem-resistant K. pneumoniae.

scholarly journals Complete Genome Sequences of Penicillin-Resistant Bacillus anthracis Strain PCr, Isolated from Bone Powder

2019 ◽  
Vol 8 (35) ◽  
Author(s):  
Akiko Okutani ◽  
Satoshi Inoue ◽  
Shigeru Morikawa
Keyword(s):  
Bacillus Anthracis ◽  
Resistant Strain ◽  
Etiologic Agent ◽  
Beta Lactam ◽  
Genome Sequences ◽  
Content Type ◽  
Beta Lactam Antibiotics ◽  
Naturally Occurring ◽  
Bone Powder ◽  
Resistant Strains

Bacillus anthracis, the etiologic agent of anthrax, is susceptible to beta-lactam antibiotics, but few cases of naturally occurring penicillin-resistant strains have been reported. We report the genome sequence of penicillin-resistant strain Bacillus anthracis PCr, isolated from imported bone powder in 1978 in Japan.

scholarly journals Full-Genome Sequencing Identifies in the Genetic Background Several Determinants That Modulate the Resistance Phenotype in Methicillin-Resistant Staphylococcus aureus Strains Carrying the Novel mecC Gene

2017 ◽  
Vol 61 (3) ◽  
Author(s):  
Catarina Milheiriço ◽  
Hermínia de Lencastre ◽  
Alexander Tomasz
Keyword(s):  
Staphylococcus Aureus ◽  
Antibiotic Resistance ◽  
Genetic Background ◽  
Beta Lactam ◽  
Methicillin Resistant ◽  
Content Type ◽  
Resistance Phenotype ◽  
Beta Lactam Antibiotics ◽  
Oxacillin Resistance ◽  
Mrsa Strains

ABSTRACT Most methicillin-resistant Staphylococcus aureus (MRSA) strains are resistant to beta-lactam antibiotics due to the presence of the mecA gene, encoding an extra penicillin-binding protein (PBP2A) that has low affinity for virtually all beta-lactam antibiotics. Recently, a new resistance determinant—the mecC gene—was identified in S. aureus isolates recovered from humans and dairy cattle. Although having typically low MICs to beta-lactam antibiotics, MRSA strains with the mecC determinant are also capable of expressing high levels of oxacillin resistance when in an optimal genetic background. In order to test the impact of extensive beta-lactam selection on the emergence of mecC-carrying strains with high levels of antibiotic resistance, we exposed the prototype mecC-carrying MRSA strain, LGA251, to increasing concentrations of oxacillin. LGA251 was able to rapidly adapt to high concentrations of oxacillin in growth medium. In such laboratory mutants with increased levels of oxacillin resistance, we identified mutations in genes with no relationship to the mecC regulatory system, indicating that the genetic background plays an important role in the establishment of the levels of oxacillin resistance. Our data also indicate that the stringent stress response plays a critical role in the beta-lactam antibiotic resistance phenotype of MRSA strains carrying the mecC determinant.

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